TCR2 Therapeutics CEO Garry Menzel, Ph.D., says immunotherapies represent “a new golden age” of medicines to treat cancer and much of the excitement surrounds their potential to cure patients, but he cautions they are not “a panacea.”

The Cambridge, Mass.–based company has developed an approach to stimulating the cancer killing capabilities of T cell therapy – different from traditional CAR-T therapy – in an effort to target what Menzel describes as the “hostile solid tumor microenvironment,” which “lends itself to driving T cell exhaustion.”

As Menzel explains, “The T cell receptor (TCR) is a remarkable structure that triggers a complex cascade of signaling when bound to tumor antigen. Finding ways to sustain T-cell activity will be crucial to immunotherapy success and that is what we are doing at TCR2.”

Menzel was named CEO of TCR2 Therapeutics in 2016, after serving as chief strategy officer at Axcella Health, chief financial officer at DaVita Healthcare, and chief operating officer at Regulus Therapeutics. He also held global leadership roles in running the biotechnology practices at Goldman Sachs and Credit Suisse. Menzel earned a Ph.D. from the University of Cambridge and an MBA from the Stanford Graduate School of Business.

WuXi AppTec Communications recently talked with Menzel about TCR2 Therapeutics’ exciting research, and the role immunotherapies will play in the difficult war on cancer. The interview is part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.

WuXi: What is TCR2 Therapeutics’ approach to cancer immunotherapy?

Garry Menzel: We are a novel cell therapy company focused on using the full power of the T-cell receptor (TCR) to cure cancer patients. We believe that this is the foundation required to overcome the hostile microenvironment of solid tumors. The TCR is a remarkable structure that triggers a complex cascade of signaling when bound to tumor antigen.  We seek to harness that power by tethering a TCR subunit to a binding domain for a specific tumor antigen. The key is that this construct is integrated as part of the TCR so that any signaling on binding to tumor antigen triggers the entire activation cascade. This is very different to a traditional CAR-T approach where the construct is expressed separately from the TCR and triggers only part of the activation cascade. As a result, we have been able to eliminate cancer cells with sustained durability in solid tumor animal studies. We call our constructs TRuCs™ (as opposed to CARs) and they are differentiated from other TCR approaches by not being restricted to antigens presented through the major histocompatibility complex (MHC). That allows our TRuCs to recognize a broad range of surface antigens in tumors and makes available a lot of good opportunities to treat cancer patients with our approach.

WuXi: What have you learned so far about immunotherapy?

Garry Menzel: Our immune system is a very powerful weapon in the fight against cancer. Its unprecedented ability to eradicate tumors has been shown by checkpoint inhibitors and cell therapies (both CD19 CAR-T in Acute Lymphoblastic Leukemia and TIL’s in Melanoma). The clinical data clearly demonstrate that we have entered a new golden age of therapies following mixed success with surgery, radiology and chemotherapy. Attend any immunotherapy conference and you will hear many different approaches being developed for a broad range of cancers. That is exciting. But you will also hear significant discussion about the challenges not least of which is the hostile solid tumor microenvironment and how to prevent cancer fighting back. The immune system is very complex and we need a better understanding of how it interacts with tumor cells to enable the very best therapies for patients.

WuXi: What are some of the shortcomings, in general, of immunotherapy?

Garry Menzel: While efficacy has been demonstrated in several cancer types leading to complete clearance of tumor cells there is still an issue with durability. This is particularly true in solid tumors where the hostile microenvironment lends itself to driving T-cell exhaustion. Finding ways to sustain T-cell activity will be crucial to immunotherapy success and that is what we are doing at TCR2 with our TRuCs. Powering T-cells through the entire TCR appears to make them more persistent.

Safety is another challenge because there is a delicate balance when activating the immune system between having just enough power to kill all the tumor cells while avoiding too much power that causes an inflammatory cascade. In cell therapy we have witnessed a number of deaths from cytokine release syndrome (CRS), for example. Having a brake as well as an accelerator may be a necessary component of future therapies.

Patient selection has also been an interesting challenge – determining which patient subsets that are most likely to respond to specific immunotherapies. Merck identified PD-L1 as a marker for their PD-1/PD-L1 inhibitor and that led to a very successful clinical trial and subsequent FDA approval for Keytruda in NSCLC. Compare that with the failure of Opdivo from Bristol-Myers where a biomarker was not used and instead a broad population of patients was treated unsuccessfully.

WuXi: Is immunotherapy the best new weapon against cancer?

Garry Menzel: It is certainly one of the most exciting weapons because it appears to have curative potential even for patients with advanced tumors. However, immunotherapy is not a panacea and is considered by physicians as simply another component of the arsenal of therapies and treatments available for patients. The advantage is that immunotherapy is highly specific and can be personalized.

WuXi: What role will combination therapies play in cancer immunotherapy?

Garry Menzel: Combination therapies will play a vital role in cancer immunotherapy. This is particularly true in solid tumors where the microenvironment is so hostile to the immune system. We have already observed patient relapses in immunotherapy due to antigen escape. And this ability of cancer cells to resist treatment has been witnessed with other targeted modalities – ALK and BTK inhibitors were limited by additional mutations as the tumors evolved. So it makes sense to hit cancer with a one-two combination punch. However, the tumor microenvironment is incredibly complex and we are at an early stage of understanding the various interrelationships at a genetic and cellular level. This will necessitate experimenting with potential combinations in real time for patients until basic research catches up and guides our focus. We believe that our TRuC T-cell therapies will be a foundation for many of these combinations as we can unleash the full killing power of the immune system only by signaling through an intact TCR.

WuXi: How does immunotherapy compare to other innovative approaches, such as epigenetics and cancer cell metabolism, which may target the cancer cell rather than the immune system?

Garry Menzel: I think of them all as lifesaving options. The more a patient has the better. Each one of these approaches, including immunotherapy, is simply one in a series of weapons in the arsenal available to physicians for treating cancer. One is not necessarily better than the other for a specific case, although I will note that immunotherapy has shown curative potential. The important point is that physicians and patients are given options.

WuXi: How do you see the cancer immunotherapy field evolving over the next five years?

Garry Menzel: The first checkpoint inhibitors have already been FDA approved and it seems likely that at the end of this year we will see the first cell therapy approved for Acute Lymphoblastic Leukemia.  That puts us on the threshold of a promising period for cancer patients.  I think that you will see a number of trends emerge in the next five years. First, you will see a shift of the cell therapy field from hematology into solid tumors using TCR-based approaches. The inability of CAR-T cells to sustain a durable response in the hostile microenvironment of solid tumors will require activating the entire TCR to harness the full killing power of T-cells. That is what we are doing in several programs with our TRuC T-cells at TCR2 Therapeutics. Second, as basic research uncovers more information on the various genetic and cellular interrelationships in the tumor microenvironment, more checkpoints will be exploited. Third, there will be a rapid increase in combination approaches, including non-immunotherapy regimens.

WuXi: Is global partnership part of your drug development strategy? Why or Why not?

Garry Menzel: Absolutely. At multiple levels. Our goal is to speed our therapies to patients by complementing our capabilities with expertise that others possess. For example, there are several global pharmaceutical companies who have deep experience with oncology clinical trial design and development, and some very specifically in the immunotherapy space. They have an excellent network for identifying and responding to clinical need. Diagnostics laboratories will also be important as we seek to profile tumor characteristics and ensure that the right patient population receives our TRuC T-cells. We have an automated manufacturing process but that is such an essential component of any cell therapy that we may seek a partner in the long-term for this as well. And working with leading academics and clinicians is already a core strategy so that we have the very best thought leaders providing insights into how we might improve and expand upon the opportunities for our platform. We have shown TRuC T-cells to be active against several tumor targets and types. Partnership is the best way to reach the broadest range of patients with our technology.

WuXi: What are the main barriers you face in bringing cancer immunotherapy to patients?

Garry Menzel: At this stage in our development, the biggest constraint is having enough capital. And it is my job as CEO to ensure that our passionate team of scientists is provided with sufficient resources to bring their great discoveries to patients.